AQP4-knockout alleviates the lipopolysaccharide-induced inflammatory response in astrocytes via SPHK1/MAPK/AKT signaling

Abstract

To date, aquaporin-4 (aQP4) has been considered as a critical contributor to neuroinflammation, but little is known about the underlying mechanism. Previous studies have shown that a critical enzyme involved in the sphingomyelin cycle, sphingosine kinase 1 (SPHK1), is implicated in inflammatory processes and contributes to chronic neuroinflammation. The present study investigated the role of AQP4 in proinflammatory cytokine release from astrocytes, with an emphasis on the SPHK1/mitogen-activated protein kinase (maPK)/protein kinase B (aK a) pathway. using primary cultures isolated from aQP4+/+ QP4 /- embryos, the production of tumor necrosis factor-α (TNF-α)/interleukin-6 (il-6) from astrocytes challenged by lipopolysaccharide (LPS) was compared. the results showed increased secretion of TNF-α/il-6 in the two groups following LPS treatment, but a significantly lower level was observed in the AQP4 -/- group compared with that in the aQP4+/+ group. although upregulation of SPHK1 was detected in the two genotypes, only a mild increase in SPHK1 was found in the aQP4-/- genotype. the phosphorylation of maPK/aKt was also confirmed to be attenuated in the aQP4-/- group, suggesting decreased maPK/aKt signaling over time in aQP4-/- astrocytes. overall, the study findings demonstrated that AQP4 deficiency alleviates proinflammatory cytokine release from astrocytes, in association with the SPHK1/maPK/aKt pathway. this data improves our understanding of AQP4 in neuroinflammatory events, highlighting a novel profile of SPHK1 as a potential target for the treatment of CNS inflammation.